SUMMARY: Effective new treatments for cognitive symptoms resulting from traumatic brain injury (TBI) in Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) Veterans are urgently needed. Mild TBI is extremely common among OEF/OIF Veterans and frequently accompanied by PTSD and depression symptoms, co-occurring disorders that contribute to increased disability and decreased quality of life. Neuroactive steroids (NS) represent promising targets for intervention for these diverse symptom domains, since a number of these molecules demonstrate pronounced neuroprotective and neurotrophic properties. The NS pregnenolone (PREG) is a logical therapeutic option, since it enhances learning and memory and also increases myelination in rodent models. PREG is an endogenous compound that is enriched in human brain and synthesized in the central nervous system, as well as in other tissues such as the adrenal. Furthermore, decreases in PREG have been associated with depressive symptoms, and its sulfated derivative increases acetylcholine release and enhances neurogenesis. PREG is also metabolized to allopregnanolone (ALLO), an anxiolytic downstream NS that is decreased in PTSD. PREG is available over-the-counter as a dietary supplement, yet randomized controlled trials (RCT) for any disorder utilizing this agent are exceedingly few and none have been conducted in TBI to date. Our preliminary data from a PREG pilot RCT for mild TBI in OEF/OIF Veterans suggest possible cognitive improvement in executive functioning (as assessed by the Tower of London test) and PTSD Cluster D symptoms such as poor sleep, irritability, anger outbursts, difficulty concentrating, hypervigilance, and increased startle response (as assessed by the Clinician-Administered PTSD Scale, CAPS). Further, neurosteroid increases post-treatment appear to predict improvements in PTSD symptoms. We thus propose an RCT in OEF/OIF veterans to confirm our initial findings in mild TBI. HYPOTHESES TO BE TESTED: 1.) PREG represents a multi-targeted treatment approach that will improve executive functioning in OEF/OIF veterans with mild TBI (as assessed by the Tower of London test) and reduce PTSD Cluster D symptoms (as assessed by the CAPS). 2.) PREG administration in OEF/OIF veterans with mild TBI will increase downstream ALLO and other GABAergic NS levels, representing potential mechanisms contributing to its therapeutic efficacy and candidate biomarkers for treatment response. METHODS: 1.) We propose an RCT of adjunctive PREG in 140 OEF/OIF veterans with mild TBI (70 per group) targeting executive functioning as assessed by the Tower of London test (10 cognitive outcome measure) and PTSD Cluster D symptoms (10 behavioral outcome measure). 2.) We will use state-of-the art mass spectrometry-based techniques to determine PREG and PREG metabolite levels at baseline and following this NS intervention, to assess if NS alterations following PREG administration predict treatment response and represent potential candidate biomarkers for this therapeutic approach. PUBLIC HEALTH RELEVANCE: There is currently a paucity of effective agents for the treatment of cognitive symptoms in mild TBI, a condition that impacts large numbers of OEF/OIF Veterans and is frequently accompanied by PTSD and depression symptoms. If our pilot study results are confirmed in the proposed randomized controlled trial, pharmacological intervention with the neurosteroid pregnenolone may represent a novel, effective, well-tolerated, and immediately accessible treatment for these symptoms. A new treatment for mild TBI could potentially lead to improved functional outcome and quality of life in OEF/OIF Veterans who have sustained this injury.